Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML. Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality. Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.
Bronchiolitis, an infection of the lower respiratory tract, is the leading cause of infant and child hospitalization in the United States. Therapeutic options for management of bronchiolitis are limited. Hypertonic saline inhalation therapy has been studied in numerous clinical trials with mixed results. In 2014, the American Academy of Pediatrics (AAP) published updated guidelines on the diagnosis and management of bronchiolitis, which include new recommendations on the use of hypertonic saline. We reviewed all published clinical trials mentioned in the 2014 AAP guidelines, as well as additional trials published since the guidelines, and critically evaluated each trial to determine efficacy, safety, and expectations of hypertonic saline inhalation therapy. A total of 2682 infants were studied over the course of 22 clinical trials. Nine trials were carried out in the outpatient/clinic/emergency department and 13 in the inpatient setting. We agree with the AAP guidelines regarding the recommendation to use nebulized hypertonic saline for infants hospitalized with bronchiolitis, with the expectation of reducing bronchiolitis scores and length of stay when it is expected to last more than 72 hours. However, we also believe there might be an advantage for hypertonic saline in reducing admission rates from the emergency department, based on close examination of the results of recent trials. This review also highlights important gaps in the available literature that need to be addressed in order to define the role of inhaled hypertonic saline therapy.INDEX TERMS: bronchiolitis, hypertonic saline, infants, pediatrics, review J Pediatr Pharmacol Ther 2016;21(1):7-26
Tigecycline has emerged as first line therapy for serious systemic infections due to important pathogens (except P. aeruginosa and Proteus sp.), including multi-drug resistant (MDR) and Gram negative bacilli (GNB), including carbapenem resistant Enterobacteriae. Tigecycline has a 'low resistance potential,' is protective against C. difficile, and is often the only antibiotic effective against MDR GNB, e.g., Klebsiella sp. Areas covered: Standard dose tigecycline therapy has been used for intra-abdominal infections, complicated skin/skin structure infections (cSSSIs), and CAP. Clinical experience with once daily high dose tigecycline (HDT), i.e., 200 - 400 mg (IV) x 1, then 100 - 200 mg (IV) q24 h, is reviewed. Optimal tigecycline efficacy is dependent on PK/PD based dosing. Suboptimal outcomes have been due to inappropriate use or suboptimal dosing. Expert commentary: Tigecycline's spectrum against nearly all important pathogens (including MSSA/MRSA, VSE/VRE, B. fragilis, C. difficile, MDR and GNB) assures tigecycline a critical place in the antibiotic armamentarium. Dosed optimally, HDT can be a cornerstone of antibiotic stewardship programs in preventing C. difficile, treating MDR GNB pathogens, and in preventing resistance. Properly used and optimally dosed, once daily HDT should be considered preferred therapy for severe systemic infections and those due to MDR GNB pathogens.
Immune checkpoints are cell surface molecules that initiate regulatory pathways which have powerful control of CD8+ cytolytic T cell activity. Antagonistic and agonistic antibodies engaging these molecules have demonstrated profound impact on immune activation and have entered clinical use for the treatment of a variety of diseases. Over the past decade, antagonistic antibodies known as immune checkpoint inhibitors have become a new pillar of cancer treatment and have reshaped the therapeutic landscape in oncology. These agents differ in their mechanism of action and toxicity profiles compared to more traditional systemic cancer treatments such as chemo‐ and targeted therapies. This article reviews the pharmacology of this new class of agents.
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